The Most Famous New Zealand Mice in the World

They are called New Zealand Obese mice, which is a bit on the nose considering that they were born in Australia and became obese eating Aussie chow, but no matter.

The mice are famous because they belong to Son Andrikopoulos, who is the president of the Australian Diabetes Society. Prof Andrikopoulos has previously used mouse research to make claims in Australian media that we should have fructose-sweetened drinks with our hamburgers to make us feel fuller.

Dietary guidelines for the past 20 years have recommended that dietary fat should be minimized. In contrast, recent studies have suggested that there could be some potential benefits for reducing carbohydrate intake in favor of increased fat. It has also been suggested that low-carbohydrate diets be recommended for people with type 2 diabetes. However, whether such diets can improve glycemic control will likely depend on their ability to improve β-cell function, which has not been studied. The objective of the study was to assess whether a low-carbohydrate and therefore high-fat diet (LCHFD) is beneficial for improving the endogenous insulin secretory response to glucose in prediabetic New Zealand Obese (NZO) mice.

METHODS:

NZO mice were maintained on either standard rodent chow [n=8] or an LCHFD [n=9] from 6 to 15 weeks of age. Body weight, food intake and blood glucose were assessed weekly. Blood glucose and insulin levels were also assessed after fasting and re-feeding and during an oral glucose tolerance test. The capacity of pancreatic β-cells to secrete insulin was assessed in vivo with an intravenous glucose tolerance test. β-Cell mass was assessed in histological sections of pancreata collected at the end of the study.

An LCHFD is unlikely to be of benefit for preventing the decline in β-cell function associated with the progression of hyperglycemia in type 2 diabetes.

Now, it is a normal finding that a LCHF diet causes weight gain and increases blood glucose in obese mice. They are different to humans in this regard. However, the effect can be reversed by a sufficiently ketogenic diet. This was discussed by Mobbs et al in 2013,[1] with a discussion of its relationship to human studies. You see, it has been known for a long time that LCHF diets improve overweight and diabetes in humans. The mouse studies are meant to shed light on the mechanisms, but rodents just aren’t a good model for humans at LCHF ratios.

However, something else happened when Prof Andrikopoulos hit the media – this LCHF mouse study became material for an attack on Pete Evans and the Paleo diet.

“New research proves eating a paleo diet for just eight weeks can lead to rapid weight gain.” was the headline in the Herald Sun.

“Lead author, Associate Prof Sof Andrikopoulos says this type of diet, exemplified in many forms of the popular Paleo diet, is not recommended – particularly for people who are already overweight and lead sedentary lifestyles.
He says mass media hype around these diets, particularly driven by celebrity chefs, celebrity weight-loss stories in the tabloid media and reality TV shows, are leading to more people trying fad diets backed by little evidence. In people with pre-diabetes or diabetes, the low-carb, high-fat (LCHF) diet could be particularly risky, he said.
Low-carbohydrate, high-fat diets are becoming more popular, but there is no scientific evidence that these diets work. In fact, if you put an inactive individual on this type of diet, the chances are that person will gain weight,” Assoc Prof Andrikopoulos, President of the Australian Diabetes Society, said.

Most of the studies we’ve seen for LCHF diets in diabetes don’t involve intense exercise regimes. We’ve seen the kilos melt off inactive people in real life. Exercise is good for health and blood sugar control, but there’s no doubt that LCHF and Paleo diets work extremely well for thousands of ordinary people who don’t have high activity levels.

We think that the way Prof Andrikopoulos presented his results in the media was disgraceful. He can’t be unaware of the human research into LCHF for diabetes and the problems with mouse models. He could easily learn, if he wanted to, about relevant research into the Paleo diet too. Absolutely none of this research supports the claims that he’s making on the basis of his 9 mice.

His claims, despite being based on minimal evidence having very limited relevance. seem designed to disrupt the efforts of those of his colleagues who are using LCHF diets to benefit people suffering from obesity or diabetes.

Can we learn something from these mice anyway?

What did the study tell us about Paleo diets?

Prof Andrikopoulos’s mouse study wasn’t designed to test the Paleo diet. Pete Evans’ version of paleo doesn’t include dairy, but the only protein the LCHF mice were fed was casein. This is one of the proteins in milk and its consumption is even linked to type 1 diabetes in some studies.

In fact, for a mouse, the control diet was more “Paleo”, if paleo means an ancestrally appropriate diet. The control mice were fed “wheat, wheat byproducts, fish meal, tallow/vegetable oil blend, soybean meal, skim milk powder, yeast, molasses” – the LCHF mice received none of these foods. They were fed sucrose (table sugar), cocoa butter, canola oil, ghee, and casein, with vitamin, mineral supplements and an amino acid that’s undersupplied in casein (DL-Methionine, which the control mice didn’t get, because the protein in their diet was nutritionally adequate).
This is a diet comparison that was very poorly controlled, if it was meant to be a comparison of carbs vs fat.

If we think that “Paleolithic diet” means “eat real foods that your ancestors ate”, rather than “eat lots of pure fats”, then Prof Andrikopoulos’s mouse study is more supportive of the Paleo diet than otherwise.

What did the study tell us about LCHF diets?

What about the LCHF finding? Prof Andrikopoulos’s “New Zealand Obese” pre-diabetic mice became significantly more overweight on an LCHF diet. Their insulin and blood glucose both became higher. This is a common effect of weight gain in people with pre-diabetes. Reduction in weight leads to lower insulin and reduction in blood sugar in overweight people with type 2 diabetes or prediabetes. A low-carbohydrate diet (but not a standard diabetes diet) even leads to improved glycemic control without weight loss if weight is kept stable.

A low-carb diet is more effective for weight loss than a low-fat calorie-restricted diet, and better for glycaemic control than the low-fat diet or the standard diabetes diet recommended by the American Diabetes Association.

What about the claim that a LCHF diet will cause someone with pre-diabetes to become diabetic?

This has been tested in humans by Maekawa et al (2014).[2] A course of low carb education was given to 36 people with impaired glucose tolerance in Japan, who were then followed for 12 months. None of these people developed diabetes (compared to 13.9% of the case-matched controls at the same hospital who received normal advice), and glucose tolerance was normalized in 69.4%, compare to 8.3% of the controls.

This wasn’t an RCT, but a retrospective case-control study; however, that doesn’t affect at all the finding that LCHF diet education, with good compliance, was not followed by the progression of pre-diabetes to diabetes in any of the 36 patients.

But if the weight (fat mass, not muscle) of an overweight person increased significantly – even on a low carb diet – glycaemic control likely would deteriorate. Significant fat gain on LCHF is pretty rare, but it can happen.

In this case study a woman with Prader-Willi syndrome (this is a genetic disease affecting nutrient partitioning and appetite, which currently has a poor prognosis no matter how it is managed) became obese and developed type 2 diabetes on a LCHF diet.[3]

What we can take away from this is perhaps, that LCHF and Paleo diets will not be much help to that rare person who becomes significantly more overweight (rather than less overweight or weight-stable) when they restrict carbohydrates, if the diet cannot be adapted to prevent this happening.

Significant weight gain in response to a low carb diet in someone already overweight seems to be very rare – fortunately it is a very simple diagnosis.

Our take home message: Mouse studies of human diseases are sometimes useful, but their use in LCHF research seems to be very limited, and can never overturn human research and clinical findings in real people.

There are COIs for sure – but the idea that dietary fat is bad for diabetes has a long history, and it’s easy to see how it makes sense to some researchers.
If you gain weight, that’s bad for diabetes, and adding fat to the normal diet increases insulin requirements and, because it’s calorie dense, is pretty good for adding weight. LCHF changes the rules – fat usually becomes slimming, and it’s well tolerated by people with diabetes when carbohydrate intake is low. It also makes it easier to a) eat less and b) eat less often, both of which are critical strategies for reversing the diabetes of overweight.
The problem is that the cautious-yet-permissive diabetes management usually applied advises people to eat just enough carbohydrate to make any extra fat in the diet unsafe. If you can’t ditch the idea that you need X amount of carbohydrate to run your brain and prevent ketosis, you can well be stuck in a place where fat is not your friend.

Good comments but “He can’t be unaware of the human research into LCHF for diabetes and the problems with mouse models” Why not? He cited all of them in his reference list which, he may have felt is enough. He probably felt that since he knows the answer he didn’t have to read them. On “We think that the way Prof Andrikopoulos presented his results in the media was disgraceful,” thou hast said it.

Thank you Professor.
I will cite Borghjid and Feinman (2012) on the mouse vs human issue here as it makes the same point as Mobbs et al (2013) without the reader having to negotiate a paywall.[1]

Andrikopoulos does indeed cite human studies en passant; but one wonders if he tried using any of the existing human studies to answer his own questions.
“an LCHFD does not necessarily result in weight reduction,
[no reference for this statement – and what happens when weight remains the same?]
and high dietary fat in animal studies, regardless of effects on body weight, has been shown to cause an increased accumulation of lipids in the liver
[this may be a difference between animals and humans, it might be good to cite some human NAFLD research here]
which negatively affects insulin’s ability to reduce hepatic glucose production
[indeed it does, wouldn’t it be great if there was a therapy that reversed fatty liver in pre-diabetic humans].

Thanks to Cliff Harvey for highlighting this finding of the study
“An LCHFD does not affect pancreatic morphology in NZO mice
An LCHFD did not affect pancreatic weight (Figure 6a) or morphology. In histological sections, insulin-containing β-cells were identified by immunohistochemistry. Analysis of these sections revealed that islet density, islet size and β-cell mass (Figures 6b–d) were not increased in mice fed an LCHFD. Thus there was no evidence that an LCHFD can have a beneficial effect on pancreatic morphology in NZO mice.
[and no evidence that it had a harmful effect when compared to the Adele Davis chow diet. If anyone cares about minor, non-significant differences, these all seem to favour the LCHFD – harm is not trending among the LCHF mice]

Even though this beta-cell finding – the novel contribution of this research – was null, the following statement is interesting
“reducing the requirement for insulin secretion appears to have significant benefits for pancreatic β-cells.”

I wonder what diet would reduce the demand for insulin secretion the most in humans.
I wonder what diet would increase it the most.
I think the insulin requirements of people with type 1 diabetes on different diets might be a useful guide here.

These are herbivore mice with a genetic mutation that removes an important part of their fat metabolism. Humans are not herbivores, more adapted to low carb high fat diets, and do not have this mutation. This mouse model is not representative of type 2 diabetes in humans.

They were on a very poorly chosen processed chow. This diet is not representative of low carb or paleo diets. Real diets from real foods are beneficial. Meat, eggs, dairy, fish, nuts, seeds, vegetables, virgin oils are all real foods. Table sugar, canola oil, and DL-Methionine are not.

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NZO mice are more obese and prone to type 2 diabetes precisely because their fat metabolism is impaired.

They lack phosphatidylcholine transfer protein (PCTP) that is important for processing of fat in the liver, heart, muscle, and kidneys. PCTP is used to transfer around fatty acids in the form of phosphatidylcholine inside cells, including into the mitochondria. If you ever heard of the importance of choline in fat burning, this is it.

They have reduced rates of gluconeogenesis, glycogenolysis, and based on this, most likely reduced rates of ketogenesis as well.

They have increased absorption, synthesis, and utilization of triglycerides, and higher storage in adipose tissue. Most likely they burn more fatty acids from triglycerides via a secondary pathway as a compensatory mechanism for the impaired fat metabolism via PCTP.

All of this means they are less suited for burning fat than getting their energy from carbohydrates.

This study is not at all relevant to humans. To quote Wikipedia: *No human patients with defects in PCTP have been described to date.*

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The chow they used also speaks for itself.

They use sucrose as the source of carbohydrates. It speaks volumes of the quality of study if they add the single most processed sugar on the world to low carbohydrate high fat diets. It simply does not belong there.

They used cocoa butter, canola oil, and ghee as the source of fat. They can’t keep out processed oils and fats from low carbohydrate chows it seems. How about using meat, eggs, dairy, fish, nuts, seeds, vegetables, and virgin oils, or REAL FOOD for once, that are actually advocated by paleo and other worthwhile diets?

Protein is only 13% instead of the standard 20%, and they used casein and methionine for the source of protein.

Casein is low in glycine, alanine, and taurine, all of which are important to counteract metabolic abnormalities induced by a poor diet, including fatty liver and diabetes.

Additional methionine is completely unnecessary, in fact detrimental, because it needs to be counteracted by additional glycine, choline, and cysteine.

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As a daily reminder, type 2 diabetes in humans is primarily caused by intake of refined and excessive carbohydrates. Study upon study shows the superiority of low carbohydrate diets in the prevention and treatment of type 2 diabetes. Bad quality studies with wrong mouse models and wrong diets will not change this.

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Finally, the authors of the study can GFT. They knew this mouse model is not representative of type 2 diabetes in humans. They knew this diet is not representative of low carb and especially paleo diets. And they knew exactly what was going to happen to these mice when fed such a diet they can not process.

They wanted to smear low carb and paleo, and did everything as wrong as they possibly could to that end.

Grant, Wouldn’t it be interesting to develop a web-based site that would essentially be a meta analysis of X, n=1 “experiments?” X would grow in time to thousands; thousands of success stories of people living the low carb, healthy fat lifestyle. From this site one could potentially develop some impressive statistics that are NOT based on lab animals but actual humans. As the saying goes, the proof will be in the pudding. Ailments reversed, lipid panels before and after, weight loss (muscle mass gained), sleep patterns, energy level, clarity (no more brain fog) – all could be recorded and studied.

I understand you’re quite busy but if you ink there is any merit to this idea I would greatly appreciate your thoughts and comments. Thanks,

From what I hear from my encounters with a vast range of people, the general public are getting the message that sugar and other refined carbs are bad news and good fats are no longer the enemy. I’d say certain food industry giants will be getting rattled and this study is part of the misinformation fight-back.